Bacterial modification of bile acids alters host physiology

Abstract

The human gut microbiome is known to play a crucial role in human energy harvest and homeostasis and has been implicated in the pathophysiology of obesity and metabolic syndromes. Defining the roles of specific microbial activities and metabolites on host phenotypes has proven challenging, however, due to the complexity of the microbiome‐host ecosystem. This lack of mechanistic understanding regarding the functions of microbial species has limited the effectiveness of both dietary and therapeutic approaches to improving host physiology. Using both genetic and chemical tools that target gut bacteria, we now report that we can selectively modulate the in vivo levels of a class of metabolites called bile acids, and that this controlled alteration of the bile acid pool exerts distinct effects on host physiology.Bile acids are steroidal metabolites that play crucial roles in host metabolism by acting both as detergents that aid in digestion and as ligands for host receptors, including nuclear hormone receptors and GPCRs. In the colon, bacteria chemically modify host‐produced primary bile acids, generating a group of approximately 50 metabolites called secondary bile acids. While imbalances in this bile acid pool have been correlated with metabolic disorders, it is unclear which bile acids exert beneficial or harmful effects on host metabolism. Here, we report that we can control the in vivo pool of bile acids in mice by inhibiting the keystone enzyme of bacterial bile acid metabolism, bile salt hydrolases (BSH). Germ‐free mice monocolonized with a BSH‐deleted strain displayed altered metabolism, including reduced weight gain and reduced respiratory exchange ratios, as well as transcriptional changes in metabolic, circadian rhythm, and immune pathways in the gut and liver. We also determined that the metabolic differences observed were not due to differential detergent abilities of the bile acid pools but rather to bile acid‐mediated signaling. These results indicate that the deletion of a single bacterial gene can profoundly alter host metabolism. In ongoing work, we have developed a small molecule pan‐inhibitor of BSH. We are currently using this inhibitor as a chemical tool to probe the effects of bacterial bile acid modifications on host metabolism in fully colonized animals.Support or Funding InformationR35 GM128618, NIH/NIGMS; 5P30DK034854‐33, NIH/NIDDK (Harvard Digestive Diseases Center); Center for Microbiome Informatics and Therapeutics at MIT Innovation Award; Karin Grunebaum Cancer Research Foundation Faculty Research Fellowship; Quadrangle Fund for Advancing and Seeding Translational Research (Q‐FASTR).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.